In eukaryotic cells, mitosis is regulated by so-called mitotic checkpoint controls. These controls ensure that mitosis does not occur until the genome is fully replicated and also contains no double-stranded DNA breaks. The checkpoint pathways thus assure that each daughter cell will contain a full copy of the parental genotype. Checkpoint controls are well characterized in fission yeast in which mitotic controls involve the M- phase enzyme (cdc2/cyclin B) and antagonistically functioning kinases (wee1/mik1) and phosphatases (cdc25) that regulate cdc2. The broad long- term objective of this proposal is to understand the mitotic checkpoint control pathways of human cells. This will involve not only the isolation of checkpoint control genes and characterization of their protein products, but also investigation of checkpoints as integrated control functions. These studies are significant for human proliferative disease because tumor cells display deficiencies in checkpoint controls and these deficiencies may be related to the relative efficacy of chemotherapeutic agents.